This proposal is a competitive renewal application which main goal is to define the mechanisms by which ischemic preconditioning (IPC) promotes neuroprotection against cerebral ischemia. The main findings in the previous funding cycle were (a) the demonstration that epsilon protein kinase C (ePKC) plays a pivotal role in the induction of tolerance after ischemic preconditioning in brain (IPC) and (b) that resveratrol (3,5,4'- trihydroxystilbene) mimics cerebral ischemic preconditioning (IPC) via SIRT1. We show in preliminary studies that ischemic-, resveratrol- and 5PKC-induced preconditioning increase the expression of the neurotrophin brain-derived neurotrophic factor (BDNF). The main goals of the new funding cycle are to define the common signaling pathways activated by resveratrol and IPC that promote ischemic tolerance. The specific aims and associated hypotheses include: 1) To define whether SIRT1 is necessary and sufficient in the induction of IPC neuroprotection. Since resveratrol may have multiple molecular targets, it is first important to define that its role in preconditioning requires activation of SIRT1; 2) To determine the downstream signaling pathways that lead to SIRT1 mediated ischemic tolerance. Our preliminary evidence demonstrates that inhibition of the BDNF receptor (TrkB) abolishes neuroprotection in each of our preconditioning paradigms. Our main hypothesis here is that IPC/RPC increases BDNF levels via the SIRT1 pathway; 3) Identification of synaptic targets and signaling pathways after preconditioning. Our hypothesis in this aim is that synaptic rearrangements underlie neuroprotection conferred by ischemic-, resveratrol (RPC)- and 5PKC (PPC)-induced preconditioning. An alternative hypothesis is that unlike IPC and PPC, RPC neuroprotection may not depend on synaptic modifications; instead the dominant effect of RPC involves direct activation of cell survival pathways; and 4) To determine whether ischemic tolerance can be induced by chronic resveratrol. The ultimate goal of this application is to provide some potential new therapies against cerebral ischemia. Our hypothesis is that chronic exposure to resveratrol results in a maintained preconditioned state similar to the single dose.